Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy.
Authors: Michael White, Christopher P. Vellano, Miles Cameron Andrews, Russell G. Witt, Manoj Chelvanambi, Jennifer Leigh McQuade, Elizabeth M. Burton, Yanshuo Chu, Matthew J Lastrapes, Mike R. Lau, Hiya Banerjee, Alexander J. Lazar, Michael A. Davies, Scott Eric Woodman, Linghua Wang, Amy E. Moran, Georgina V. Long, Timothy Heffernan, Joe R. Marszalek, Jennifer Ann Wargo
Journal: Journal of Clinical Oncology (2022)

9523 Background: Treatment with BRAF+/-MEK inhibition (BRAF+/-MEKi) has revolutionized treatment in melanoma and other cancers, but resistance is common and innovative treatment strategies are needed. Sexual dimorphism in response to BRAF+/-MEKi have been noted, but mechanisms behind this are poorly understood and hormonal modulation has not been well-studied in this setting. Methods: We examined outcomes by sex in five clinical cohorts of patients (pts) (total n = 792, 362 female, 430 male) with BRAF-mutated melanoma who were treated with BRAF/MEKi in either the neoadjuvant or metastatic setting. Rates of major pathologic response (MPR), clinical benefit (CB), progression free survival (PFS) relapse-free survival (RFS) and overall survival (OS) were assessed. Translational research studies were performed on available pre- and on-treatment tumor samples (n = 27 pts) including RNA sequencing and profiling androgen receptor (AR) expression. Parallel studies were performed in preclinical models to assess the effect of sex and AR modulation on response to BRAF+/-MEKi. Results: In this study, improved rates of MPR, CB, PFS and OS were observed in female vs male pts. Specifically, female patients treated with neoadjuvant BRAF+MEKi showed significantly higher rates of MPR (66% v. 14%, p = 0.001), and improved RFS (64% versus 32% at 2 years, p = 0.021) vs male pts in the neoadjuvant setting (n = 51). These findings were not observed in a 2 nd smaller trial of pts (n = 35), but were validated in a cohort of pts with unresectable metastatic melanoma treated with BRAF+MEKi (n = 69), with significantly higher rates of CB (80% v. 68%, p = 0.022) and PFS (12 v. 7 months, p = 0.003) in female vs male pts. Data from several published trials was analyzed (COMBI-D and METRIC trials), demonstrating improved PFS/OS at 2 years in female vs male pts treated with combined BRAF/MEKi (n = 211; p = 0.03 and, p = 0.04) and in female vs male pts treated with MEKi monotherapy (n = 206; p = 0.04 and p = 0.002), but not in female vs male pts treated with BRAFi monotherapy (n = 211; p = 0.21 and 0.095). Significantly higher expression AR expression was observed in available on- vs pre-treatment samples from male pts (p = 0.01), suggesting that treatment with BRAF/MEKi may induce AR expression in tumors. Findings were recapitulated in several preclinical models, and treatment with pharmacologic inhibitors of AR signaling (enzalutamide) in combination with BRAF/MEKi was associated with significantly enhanced anti-tumor activity in both male and female mice (p = 0.003 and p &lt; 0.0001). Conversely, systemic treatment with testosterone was associated with significantly impaired tumor control in male and female mice (p = 0.021 and &lt; 0.001). Conclusions: These data suggest that AR blockade may promote BRAF/MEKi response in melanoma, warranting further investigation in clinical trials. The impact of AR signaling, and modulation should be studied in MAPK-targeted therapy across other cancer types.